tbuckley/cabot-search huggingface dataset:
Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study
Authors: Shukui Qin, Stephen L Chan, Shanzhi Gu, Yuxian Bai, Zhenggang Ren, Xiaoyan Lin, Zhendong Chen, Weidong Jia, Yongdong Jin, Yabing Guo, Xiaohua Hu, Zhiqiang Meng, Jun Liang, Ying Cheng, Jianping Xiong, Hong Ren, Fang Yang, Wei Li, Yajin Chen, Yong Zeng, Alexander Sultanbaev, Monika Pazgan-Simon, Margaryta Pisetska, Davide Melisi, Dmitriy Ponomarenko, Yurii Osypchuk, Ivan Sinielnikov, Tsai-Sheng Yang, Xiao Liang, Chunxia Chen, Linna Wang, Ann-Lii Cheng, Ahmed Kaseb, Arndt Vogel, Shukui Qin, Stephen L Chan, Ann-Lii Cheng, Ahmed Kaseb, Arndt Vogel, Shanzhi Gu, Yuxian Bai, Zhenggang Ren, Xiaoyan Lin, Zhendong Chen, Weidong Jia, Yongdong Jin, Yabing Guo, Xiaohua Hu, Zhiqiang Meng, Jun Liang, Ying Cheng, Jianping Xiong, Hong Ren, Fang Yang, Wei Li, Yajin Chen, Yong Zeng, Alexander Sultanbaev, Monika Pazgan-Simon, Margaryta Pisetska, Davide Melisi, Dmitriy Ponomarenko, Yurii Osypchuk, Ivan Sinielnikov, Tsai-Sheng Yang, Xiao Liang, Chunxia Chen, Linna Wang, Mingxiang Zhang, Li Xu, Xianglin Yuan, Da Li, Jierer Ying, Jingdong Zhang, Tao Zhang, Kangsheng Gu, Yifu He, Ping Hao, Da Jiang, Shu Zhang, Baocai Xing, Baihong Zhang, Dong Wang, Xiaofeng Zhai, Houjie Liang, Bozena Cybulska-Stopa, Mikhail Dvorkin, Daniil Stroyakovskiy, Marina Nechaeva, Chia-Jui Yen, Wei-Wen Su, Yen-Hao Chen, Igor Bondarenko, Lin Yang, Weijia Fang, Carlos Gomez-Martin, Min-Hee Ryu, Han-Sang Kim, Jee-Hyun Kim, Oleg Zarubenkov, Rashida Orlova, Elena Poddubskaya, Natalia Fadeeva, Yulia Makarova, Yee Chao, Chao-Hung Hung, Maryna Neffa, Oleksandr Vynnychenko, Adam Burgoyne, Chunyi Hao, Raphael U Mohr, Roberto Diaz-Beveridge, Jaime Feliu-Batlle, Antonio Cubillo-Gracian, Ann-Shing Lee, Bruno Daniele, Lorenzo Antonuzzo, Angelo Sangiovanni, Antonio Gasbarrini, Mario Scartozzi, Mi Sun Ahn, Sung-Yong Oh, Sergey Orlov, Hakan Harputluoglu, Berna Oksuzoglu, Chiun Hsu, Kun-Ming Rau, Oleksandr Krechkovskyi, Vladimir Yareshko, Henry Xiong, Fa-Chyi Lee, Yixing Jiang, Afshin Gabayan, Mary Crow, Christophe Van Steenkiste, Gontran Verset
Journal: The Lancet (2023)
Preparing for Future Pandemics and Public Health Emergencies: An American College of Physicians Policy Position Paper
Authors: Josh Serchen, Katelan Cline, Suja Mathew, David Hilden, Suja Mathew, David Hilden, Micah Beachy, William Curry, Matthew Hollon, Cynthia Jumper, Pranav Mellacheruvu, Marianne Parshley, Ankita Sagar, Jamar Slocum, Michael Tan, Vanessa Van Doren, Elham Yousef
Journal: Annals of Internal Medicine (2023)

The onset of the COVID-19 pandemic revealed significant gaps in the United States' pandemic and public health emergency response system. At the federal level, government responses were undercut by a lack of centralized coordination, inadequately defined responsibilities, and an under-resourced national stockpile. Contradictory and unclear guidance throughout the early months of the pandemic, along with inconsistent funding to public health agencies, also created notable variance in state and local responses. The lack of a coordinated response added pressure to an already overwhelmed health care system, which was forced to resort to rationing care and personal protective equipment, creating moral distress and trauma for health care workers and their patients. Despite these severe shortcomings, the COVID-19 pandemic also highlighted successful policies and approaches, such as Operation Warp Speed, which led to the fastest development and distribution of a vaccine in history. In this position paper, the American College of Physicians (ACP) offers several policy recommendations for enhancing federal, state, and local preparedness for future pandemic and public health emergencies. This policy paper builds on various statements produced by ACP throughout the COVID-19 pandemic, including on the ethical distribution of vaccinations and resources, conditions to resume economic and social activity, and efforts to protect the health and well-being of medical professionals, among others.
Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial
Authors: Fernanda Mosele, Elise Deluche, Amelie Lusque, Loïc Le Bescond, Thomas Filleron, Yoann Pradat, Agnes Ducoulombier, Barbara Pistilli, Thomas Bachelot, Frederic Viret, Christelle Levy, Nicolas Signolle, Alexia Alfaro, Diep T. N. Tran, Ingrid Judith Garberis, Hugues Talbot, Stergios Christodoulidis, Maria Vakalopoulou, Nathalie Droin, Aurelie Stourm, Maki Kobayashi, Tomoya Kakegawa, Ludovic Lacroix, Patrick Saulnier, Bastien Job, Marc Deloger, Marta Jimenez, Celine Mahier, Vianney Baris, Pierre Laplante, Patricia Kannouche, Virginie Marty, Magali Lacroix-Triki, Veronique Diéras, Fabrice André
Journal: Nature Medicine (2023)

The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).
Trends in laboratory-confirmed bacterial meningitis (2012–2019): national observational study, England
Authors: Sathyavani Subbarao, Sonia Ribeiro, Helen Campbell, Ifeanyichukwu Okike, Mary E. Ramsay, Shamez N. Ladhani
Journal: The Lancet Regional Health - Europe (2023)

Bacterial meningitis is associated with significant morbidity and mortality worldwide. We aimed to describe the epidemiology, aetiology, trends over time and outcomes of laboratory-confirmed bacterial meningitis in England during 2012-2019.UK Health Security Agency routinely receives electronic notifications of confirmed infections from National Health Service hospital laboratories in England. Data were extracted for positive bacterial cultures, PCR-positive results for Neisseria meningitidis or Streptococcus pneumoniae from cerebrospinal fluid and positive blood cultures in patients with clinical meningitis.During 2012-19, there were 6554 laboratory-confirmed cases. Mean annual incidence was 1.49/100,000, which remained stable throughout the surveillance period (p = 0.745). There were 155 different bacterial species identified, including 68.4% (106/1550) Gram-negative and 31.6% (49/155) Gram-positive bacteria. After excluding coagulase-negative staphylococci (2481/6554, 37.9%), the main pathogens causing meningitis were Streptococcus pneumoniae (811/4073, 19.9%), Neisseria meningitidis (497/4073, 12.2%), Staphylococcus aureus (467/4073, 11.5%), Escherichia coli (314/4073, 7.7%) and group B streptococcus (268/4073, 6.6%). Pneumococcal meningitis incidence increased significantly during 2012-9, while meningococcal, group A streptococcal and tuberculous meningitis declined. Infants aged <3 months had the highest mean incidence (55.6/100,000; 95% CI, 47.7-63.5) driven mainly by group B streptococci, followed by 3-11 month-olds (8.1/100,000; 95% CI 7.1-9.0), where pneumococcal and meningitis predominated. The 30-day case-fatality rate (CFR) was 10.0% (71/6554). Group A streptococcal meningitis had the highest CFR (47/85, 55.3%). The probability of surviving at 30 days was 95.3% (95% CI, 93.4-97.3%) for infants and 80.0% for older adults (77-84%).The incidence of bacterial meningitis has remained stable. The high CFR highlights a need for prevention through vaccination.PHE.
Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement
Authors: Hye-Sook Han, Eunyong Ahn, Eun Seo Park, Tom Huh, Seri Choi, Yongmin Kwon, Byeong Hun Choi, Jueun Lee, Yoon Ha Choi, Yujin L. Jeong, Gwang Bin Lee, Minji Kim, Je Kyung Seong, Hyun Mu Shin, Hang-Rae Kim, Myeong Hee Moon, Jong Kyoung Kim, Geum-Sook Hwang, Seung-Hoi Koo
Journal: Nature Aging (2023)
Combination Lipid-Lowering Therapy in Patients Undergoing Percutaneous Coronary Intervention
Authors: Seung-Jun Lee, Jae Hong Joo, Sohee Park, Choongki Kim, Dong-Woo Choi, Sung-Jin Hong, Chul-Min Ahn, Jung-Sun Kim, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Chung-Mo Nam, Myeong-Ki Hong
Journal: Journal of the American College of Cardiology (2023)
Admission blood eosinophil count, inpatient death and death at 1 year in exacerbating patients with COPD
Authors: Carlos Echevarria, John Steer, Arun Prasad, Jennifer K Quint, Stephen C Bourke
Journal: Thorax (2023)

Background Blood eosinophil counts have been studied in patients with stable chronic obstructive pulmonary disease (COPD) and are a useful biomarker to guide inhaled corticosteroid use. Less is known about eosinophil counts during severe exacerbation. Methods In this retrospective study, 2645 patients admitted consecutively with COPD exacerbation across six UK hospitals were included in the study, and the clinical diagnosis was confirmed by a respiratory specialist. The relationship between admission eosinophil count, inpatient death and 1-year death was assessed. In a backward elimination, Poisson regression analysis using the log-link function with robust estimates, patients’ markers of acute illness and stable-state characteristics were assessed in terms of their association with eosinopenia. Results 1369 of 2645 (52%) patients had eosinopenia at admission. Those with eosinopenia had a 2.5-fold increased risk of inpatient death compared with those without eosinopenia (12.1% vs 4.9%, RR=2.50, 95% CI 1.88 to 3.31, p&lt;0.001). The same mortality risk with eosinopenia was seen among the subgroup with pneumonic exacerbation (n=788, 21.3% vs 8.5%, RR=2.5, 95% CI 1.67 to 2.24, p&lt;0.001). In a regression analysis, eosinopenia was significantly associated with: older age and male sex; a higher pulse rate, temperature, neutrophil count, urea and C reactive protein level; a higher proportion of patients with chest X-ray consolidation and a reduced Glasgow Coma Score; and lower systolic and diastolic blood pressure measurements and lower oxygen saturation, albumin, platelet and previous admission counts. Discussion During severe COPD exacerbation, eosinopenia is common and associated with inpatient death and several markers of acute illness. Clinicians should be cautious about using eosinophil results obtained during severe exacerbation to guide treatment decisions regarding inhaled corticosteroid use.
Prioritizing genes associated with brain disorders by leveraging enhancer-promoter interactions in diverse neural cells and tissues
Authors: Xingzhong Zhao, Liting Song, Anyi Yang, Zichao Zhang, Jinglong Zhang, Yucheng T. Yang, Xing-Ming Zhao
Journal: Genome Medicine (2023)

Abstract Background Prioritizing genes that underlie complex brain disorders poses a considerable challenge. Despite previous studies have found that they shared symptoms and heterogeneity, it remained difficult to systematically identify the risk genes associated with them. Methods By using the CAGE (Cap Analysis of Gene Expression) read alignment files for 439 human cell and tissue types (including primary cells, tissues and cell lines) from FANTOM5 project, we predicted enhancer-promoter interactions (EPIs) of 439 cell and tissue types in human, and examined their reliability. Then we evaluated the genetic heritability of 17 diverse brain disorders and behavioral-cognitive phenotypes in each neural cell type, brain region, and developmental stage. Furthermore, we prioritized genes associated with brain disorders and phenotypes by leveraging the EPIs in each neural cell and tissue type, and analyzed their pleiotropy and functionality for different categories of disorders and phenotypes. Finally, we characterized the spatiotemporal expression dynamics of these associated genes in cells and tissues. Results We found that identified EPIs showed activity specificity and network aggregation in cell and tissue types, and enriched TF binding in neural cells played key roles in synaptic plasticity and nerve cell development, i.e., EGR1 and SOX family. We also discovered that most neurological disorders exhibit heritability enrichment in neural stem cells and astrocytes, while psychiatric disorders and behavioral-cognitive phenotypes exhibit enrichment in neurons. Furthermore, our identified genes recapitulated well-known risk genes, which exhibited widespread pleiotropy between psychiatric disorders and behavioral-cognitive phenotypes (i.e., FOXP2), and indicated expression specificity in neural cell types, brain regions, and developmental stages associated with disorders and phenotypes. Importantly, we showed the potential associations of brain disorders with brain regions and developmental stages that have not been well studied. Conclusions Overall, our study characterized the gene-enhancer regulatory networks and genetic mechanisms in the human neural cells and tissues, and illustrated the value of reanalysis of publicly available genomic datasets.
Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Authors: Michael Chiorazzi, Jan Martinek, Bradley Krasnick, Yunjiang Zheng, Keenan J Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Melani Juric, Laura A Henze, Frederic Brösecke, Adam Adonyi, Jun Zhao, Liang Shan, Esen Sefik, Jacqueline Mudd, Ye Bi, S Peter Goedegebuure, Malachi Griffith, Obi Griffith, Abimbola Oyedeji, Sofia Fertuzinhos, Rolando Garcia-Milian, Daniel Boffa, Frank Detterbeck, Andrew Dhanasopon, Justin Blasberg, Benjamin Judson, Scott Gettinger, Katerina Politi, Yuval Kluger, Karolina Palucka, Ryan C Fields, Richard A Flavell
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. Method With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient’s hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual’s TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. Results Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. Conclusions Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.
Correction: Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial
Journal: Journal for ImmunoTherapy of Cancer (2023)

Correction: Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer
An agonistic anti-signal regulatory protein α antibody for chronic inflammatory diseases
Authors: Markus M. Xie, Bingbing Dai, Jason A. Hackney, Tianhe Sun, Juan Zhang, Janet K. Jackman, Surinder Jeet, Ricardo A. Irizarry-Caro, Yongyao Fu, Yuxin Liang, Hannah Bender, Eliah R. Shamir, Mary E. Keir, Jack Bevers, Gerald Nakamura, Michael J. Townsend, David A. Fox, Alexis Scherl, Wyne P. Lee, Flavius Martin, Paul J. Godowski, Rajita Pappu, Tangsheng Yi
Journal: Cell Reports Medicine (2023)

Signal regulatory protein (SIRPα) is an immune inhibitory receptor expressed by myeloid cells to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPα and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether SIRPα receptor agonism could restrain excessive autoimmune tissue inflammation. Here, we report that neutrophil- and monocyte-associated genes including SIRPA are increased in inflamed tissue biopsies from patients with rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA is associated with treatment-refractory ulcerative colitis. We next identify an agonistic anti-SIRPα antibody that exhibits potent anti-inflammatory effects in reducing neutrophil and monocyte chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPα agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis by reducing neutrophils and monocytes in tissues. Our work provides a proof of concept for SIRPα receptor agonism for suppressing excessive innate immune activation and chronic inflammatory disease treatment.
Efficacy of PD-(L)1 blockade monotherapy compared with PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: a cohort study
Authors: Arielle Elkrief, Joao M Victor Alessi, Biagio Ricciuti, Samantha Brown, Hira Rizvi, Isabel R Preeshagul, Xinan Wang, Federica Pecci, Alessandro Di Federico, Giuseppe Lamberti, Jacklynn V Egger, Jamie E Chaft, Charles M Rudin, Gregory J Riely, Mark G Kris, Marc Ladanyi, Yuan Chen, Matthew D Hellmann, Ronglai Shen, Mark M Awad, Adam J Schoenfeld
Journal: Journal for ImmunoTherapy of Cancer (2023)

Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO. This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores. The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO. While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification.
PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke
Authors: Akari Nakamura, Seiichiro Sakai, Yoshitaka Taketomi, Jun Tsuyama, Yoshimi Miki, Yuichiro Hara, Nobutaka Arai, Yuki Sugiura, Hideya Kawaji, Makoto Murakami, Takashi Shichita
Journal: Neuron (2023)
Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial
Authors: Cory A Perugino, Zachary S Wallace, Debra J Zack, Shauna M Quinn, Allen Poma, Ana D Fernandes, Paul Foster, Steve DeMattos, Bart Burington, Hang Liu, Hugues Allard-Chamard, Nathan Smith, Xin Kai, Kelly Xing, Shiv Pillai, John H Stone
Journal: The Lancet Rheumatology (2023)
Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions
Authors: Renhe Luo, Jielin Yan, Jin Woo Oh, Wang Xi, Dustin Shigaki, Wilfred Wong, Hyein S. Cho, Dylan Murphy, Ronald Cutler, Bess P. Rosen, Julian Pulecio, Dapeng Yang, Rachel A. Glenn, Tingxu Chen, Qing V. Li, Thomas Vierbuchen, Simone Sidoli, Effie Apostolou, Danwei Huangfu, Michael A. Beer
Journal: Nature Genetics (2023)
Graded expression of the chemokine receptor CX3CR1 marks differentiation states of human and murine T cells and enables cross-species interpretation
Authors: Anthonie Johan Zwijnenburg, Jyoti Pokharel, Renata Varnaitė, Wenning Zheng, Elena Hoffer, Iman Shryki, Natalia Ramirez Comet, Marcus Ehrström, Sara Gredmark-Russ, Liv Eidsmo, Carmen Gerlach
Journal: Immunity (2023)

T cells differentiate into functionally distinct states upon antigen encounter. These states are delineated by different cell surface markers for murine and human T cells, which hamper cross-species translation of T cell properties. We aimed to identify surface markers that reflect the graded nature of CD8+ T cell differentiation and delineate functionally comparable states in mice and humans. CITEseq analyses revealed that graded expression of CX3CR1, encoding the chemokine receptor CX3CR1, correlated with the CD8+ T cell differentiation gradient. CX3CR1 expression distinguished human and murine CD8+ and CD4+ T cell states, as defined by migratory and functional properties. Graded CX3CR1 expression, refined with CD62L, accurately captured the high-dimensional T cell differentiation continuum. Furthermore, the CX3CR1 expression gradient delineated states with comparable properties in humans and mice in steady state and on longitudinally tracked virus-specific CD8+ T cells in both species. Thus, graded CX3CR1 expression provides a strategy to translate the behavior of distinct T cell differentiation states across species.